A woman has been taking Treo comp 10-12 tablets a day (one tablet is 0.5 gram ASA + 30 mg codeine a

Fråga: A woman has been taking Treo comp 10-12 tablets a day (one tablet is 0.5 gram ASA + 30 mg codeine and 50 mg caffeine) for 2 years. Now she stopped the drug and received a standard treatment of dextropropoxyphene for one week starting with 400 mg per day and gradually decreasing to zero. Two days after the stop of dextropropoxyphene, the patient felt bad with sweating and anxiety.

Could codeine give rise to effects like sweating, anxiety and uncomfortable feeling one week after withdrawal of the drug?

Sammanfattning: There are case reports showing that codeine is addictive. Severe abstinence usually occurs within 30 hours. The kinetic study of long-term use of codeine is missing. The available kinetic data could not explain the delay of the abstinence symptoms in the present case. Still the possibility that the symptoms of the patient were due to the effect of the long term use of codeine could not be excluded.

Svar: Removal of opiate from someone who is addicted will result in an abstinence including a complex of symptoms such as yawning, rhinorrhea, mydriasis, nausea, vomiting, diarrhea, and weight loss (1).

Codeine is an over the-counter-drug in Sweden. Its addictive potential has not been conclusively proven by existing studies which suffer from poor methodology, small sample size and lack of statistical analysis (see reference 1). However, there are some case reports showing that codeine is addictive. Severe abstinence usually occurs in 30 hours and could remain for 3 to 4 days when the drug is discontinued (see reference 1).

Codeine is mainly metabolised by conjugation which is an efficient metabolic reaction. The half-life of codeine is only 2.5-3 hours (2). Kinetic data of long-term use of codeine are missing. However, the glucuronidation reactions of morphine and codeine are suggested to be under the catalysis of similar glucuronyltransferase (3). It has been shown that the glucuronidation of morphine is neither subject to autoinduction nor saturation, even after very long periods of continuous treatment with increasing doses. It was considered unlikely that metabolic tolerance would contribute to any great extent to the development of morphine tolerance in man (4).

Minor parts of codeine undergo O- and N-demethylation and give rise to active metabolites such as morphine, morphine-6-glucuronide, normorphine and norcodeine. The half-lives of these metabolites are longer than that of codeine (about 10 hours), but with minimum accumulation on multiple dosing (5). Long term kinetic study, however is needed. 1 Rowden AM, Lopez JR: Codeine addiction. DICP 1989; 23: 475-477 2 Goodman and Gilman, The pharmacological basis of therapeutics. 1985; 7th ed: 596 3 Yue Q, von Bahr C, Odar-Cederlöf I, Säwe J: Glucuronidation of codeine and morphine in human liver and kidney microsomes: effect of inhibitors. Pharmacol Toxicol 1990; 66: 221-226 4 Säwe J, Svensson JO, Rane A: Morphine metabolism in cancer patients on increasing oral doses - no evidence for autoinduction or dose-dependence. Br J Clin Pharmacol 1983; 16: 85-93 5 Yue QY, Hasselström J, Svensson JO, Säwe J: unpublished data